The purpose of this phase II clinical trial is to see if the combination of two chemotherapy drugs, treosulfan and fludarabine phosphate with or without low dose radiation, just prior to stem cell transplantation is safe and effective in patients with nonmalignant (noncancerous) diseases. Hematopoietic cell transplantation has been shown to be curative for many patients with nonmalignant (noncancerous) diseases such as primary immunodeficiency disorders, bone marrow failure syndromes, hemoglobinopathies, and inborn errors of metabolism (metabolic disorders). Powerful chemotherapy drugs and/or radiation are often used to condition the patient before infusion of the new healthy donor cells. The purpose of the conditioning therapy is to destroy the patient's abnormal bone marrow which doesn't work properly in order to make way for the new healthy donor cells which functions normally. Although effective in curing the patient's disease, many hematopoietic cell transplantation regimens use intensive chemotherapy and/or radiation which can be quite toxic, have significant side effects, and can potentially be life-threatening. Investigators at the Fred Hutchinson Cancer Research Center in collaboration with Oregon Health & Sciences University, Vanderbilt University, and Medical College of Wisconsin are investigating whether a new conditioning regimen that uses less intensive drugs (treosulfan and fludarabine phosphate) with or without low dose radiation results in engraftment of the new donor cells without increased toxicities in patients with nonmalignant (noncancerous) diseases.

Further study details as provided by Fred Hutchinson Cancer Research Center:

Primary Outcome Measures:

Preliminary efficacy as defined by engraftment of a regimen consisting of treosulfan and fludarabine phosphate followed by allogeneic HCT in patients with nonmalignant inherited disorders [ Time Frame: 1 year following transplant ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Non-relapse mortality [ Time Frame: Up to 1 year following transplant ] [ Designated as safety issue: No ]

Incidence of grade II-IV acute GVHD [ Time Frame: Within the first year following transplant ] [ Designated as safety issue: No ]

Incidence of chronic GVHD [ Time Frame: Within the two years (on average) following transplant ] [ Designated as safety issue: No ]

Donor chimerism [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]

Peripheral blood chimerism for CD3, CD33, CD19, and CD56 will be evaluated.

Disease response following HCT [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]

Immune reconstitution following HCT [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]

Measured using samples of peripheral blood, and bone marrow aspirate.

Incidence of infections [ Time Frame: Within the first year following transplant ] [ Designated as safety issue: No ]

Overall survival [ Time Frame: Within the two years following transplant ] [ Designated as safety issue: No ]

See Detailed Description. Patients undergoing bone marrow or PBSC transplantation receive tacrolimus IV continuously or PO twice daily on days -1 to 50 followed by a taper until day 180 in the absence of GVHD. Patients also receive methotrexate IV on days 1, 3, 6, and 11.

Drug: treosulfan

Given IV

Other Names:

dihydroxybusulfan

Ovastat

tresulfon

Drug: fludarabine phosphate

Given IV

Other Names:

2-F-ara-AMP

Beneflur

Fludara

Biological: anti-thymocyte globulin

Given IV

Other Names:

ATG

ATGAM

lymphocyte immune globulin

Thymoglobulin

Procedure: allogeneic bone marrow transplantation

Infused IV

Other Names:

bone marrow therapy, allogeneic

bone marrow therapy, allogenic

transplantation, allogeneic bone marrow

transplantation, allogenic bone marrow

Procedure: peripheral blood stem cell transplantation

Infused IV

Other Names:

PBPC transplantation

PBSC transplantation

peripheral blood progenitor cell transplantation

transplantation, peripheral blood stem cell

Drug: tacrolimus

Given IV or PO

Other Names:

FK 506

Prograf

Drug: methotrexate

Given IV

Other Names:

amethopterin

Folex

methylaminopterin

Mexate

MTX

Other: laboratory biomarker analysis

Correlative studies

Experimental: Group II (UBCT)

See Detailed Description. Patients undergoing UCB transplantation receive cyclosporine IV over 1 hour every 8-12 hours on days -3 to 100 followed by a taper until day 180 in the absence of GVHD. Patients also receive mycophenolate mofetil IV or PO every 8 hours on days 0 to 40 followed by a taper until day 96 in the absence of GVHD.

Drug: treosulfan

Given IV

Other Names:

dihydroxybusulfan

Ovastat

tresulfon

Drug: fludarabine phosphate

Given IV

Other Names:

2-F-ara-AMP

Beneflur

Fludara

Biological: anti-thymocyte globulin

Given IV

Other Names:

ATG

ATGAM

lymphocyte immune globulin

Thymoglobulin

Radiation: total-body irradiation

Undergo total body irradiation

Other Name: TBI

Procedure: umbilical cord blood transplantation

Single or double unit umbilical cord blood transplant, infused IV

Other Names:

cord blood transplantation

transplantation, umbilical cord blood

UCB transplantation

Drug: cyclosporine

Given IV or PO

Other Names:

ciclosporin

cyclosporin

cyclosporin A

CYSP

Sandimmune

Drug: mycophenolate mofetil

Given IV or PO

Other Names:

Cellcept

MMF

Other: laboratory biomarker analysis

Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To evaluate, within the limits of a phase II study, the preliminary efficacy, as defined by engraftment, of a regimen consisting of treosulfan and fludarabine (fludarabine phosphate) followed by allogeneic hematopoietic cell transplantation (HCT) in patients with nonmalignant inherited disorders.

SECONDARY OBJECTIVES:

I. To evaluate the incidence of non-relapse mortality 200 days and 1 year post-HCT.

III. To evaluate the incidence of chronic GVHD as defined as those patients requiring systemic immunosuppression.

IV. To evaluate donor chimerism on days +28 and +100.

V. To assess disease response following HCT.

VI. To evaluate immune reconstitution following HCT.

VII. To evaluate the incidence of infections.

VIII. To evaluate overall survival.

OUTLINE:

CONDITIONING REGIMEN: Patients receive treosulfan intravenously (IV) over 2 hours on days -6 to -4 and fludarabine phosphate IV over 1 hour on days -6 to -2. Patients receive anti-thymocyte globulin IV over 4-6 hours on days -4 to -2. Patients undergoing umbilical cord blood transplantation will also receive low dose total-body irradiation on day -1.

TRANSPLANTATION: Patients will receive either bone marrow, peripheral blood stem cells (PBSC), or umbilical cord blood from the donor on day 0. The use of either bone marrow, PBSC, or umbilical cord blood will depend on the donor status.

IMMUNOSUPPRESSION: Patients will receive a combination of immunosuppressive medications to try and prevent graft-versus-host disease. If patients undergo bone marrow or PBSC transplantation, tacrolimus and methotrexate will be used. If patients undergo cord blood transplantation, cyclosporine and mycophenolate mofetil will be used. In general, patients will receive immunosuppression until at least 180 days after transplantation; however they could be on immunosuppression longer if they develop graft versus host disease.

After completion of study treatment, patients are followed up periodically for 5 years.

Eligibility

Ages Eligible for Study:

up to 54 Years

Genders Eligible for Study:

Both

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Patients with a nonmalignant disease treatable by allogeneic HCT

Patients with a known nonmalignant disease that is not clearly defined will need to be discussed with the protocol principal investigator (PI) (Dr. Lauri Burroughs) and potentially the nonmalignant board to determine if they are eligible for HCT on this study

DONOR: Human leukocyte antigens (HLA)-identical related donors or unrelated donors matched for HLA-A, B, C, DRB1, and DQB1 or mismatched for a single allele at HLA-A, B, C, DRB1 or a single DQB1 antigen or allele mismatch by high resolution deoxyribonucleic acid (DNA) typing

DONOR: Bone marrow is the preferred cell source; PBSC are allowed if donor refuses or is unable to give marrow

DONOR: Umbilical Cord Blood: Unit selection is based on the cryopreserved total nucleated cell (TNC) dose and matching at HLA-A, B antigen level and DRB1 allele level typing; while HLA-C antigen/allele level typing is not considered in the matching criteria, if available, may be used to optimize unit selection

DONOR: Umbilical Cord Blood: The patient and the cord blood unit(s) must be matched for at least 4 of 6 loci as defined above

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Please refer to this study by its ClinicalTrials.gov identifier: NCT00919503